Enzymes accelerate organic chemical reactions by 10-20 powers of ten over their closest test-tube counterparts. In order to account for this remarkable catalytic power of enzymes, it is usually considered that the activation free energy is contributed both by binding of the substrate to the enzyme (step 1) and by chemical transformation of the bound substrate (bond-making and breaking, step 2). Popular opinion holds that most of the activation energy is supplied in step 2. We have proposed, however, that the overall catalytic process is more easily justified on the assumption that the first step contributes a more significant share of the activation energy than is generally accepted. To support this theory, we have synthesized a large variety of test-tube models which stimulate the bound substrate by being frozen into a single, very favorable conformation and by having the interacting groups brought into closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions (independently of any functional assistance) at rates comparable to those catalyzed by enzymes, and show that the protein raises both the entropic and enthalpic components of the substrate by binding it in a single, rigid conformation. Recent work has involved a study of steric and electronic effects on NMR and IR spectra across tight space rather than through covalent bonds. These studies show that kinetic and spectral properties are linearly related to the van der Waals size of crowding substituents. The upper limit of energy-related steric crowding could not be evaluated, however, because of inability to introduce the very bulky iodo group. After considerable effort, this goal has been reached and further work is in progress. As part of our studies of practical application of stereopopulation control, we have been exploring the use of o-nitroaryl derivatives of biogenic amines and antibiotics as prodrugs. The intent is to facilitate transport from the gut to the circulatory system to the brain by the temporary masking of charge within the molecule, by improvement in lipophilicity and by regeneration based simply on local pH variation in receptor sites.